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CNS & Neurological Disorders - Drug Targets

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ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

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Mini-Review Article

Curbing Rhes Actions: Mechanism-based Molecular Target for Huntington’s Disease and Tauopathies

Author(s): Srinivasa Subramaniam* and Siddaraju Boregowda

Volume 23, Issue 1, 2024

Published on: 20 April, 2023

Page: [21 - 29] Pages: 9

DOI: 10.2174/1871527322666230320103518

Price: $65

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Abstract

A highly interconnected network of diverse brain regions is necessary for the precise execution of human behaviors, including cognitive, psychiatric, and motor functions. Unfortunately, degeneration of specific brain regions causes several neurodegenerative disorders, but the mechanisms that elicit selective neuronal vulnerability remain unclear. This knowledge gap greatly hinders the development of effective mechanism-based therapies, despite the desperate need for new treatments. Here, we emphasize the importance of the Rhes (Ras homolog-enriched in the striatum) protein as an emerging therapeutic target. Rhes, an atypical small GTPase with a SUMO (small ubiquitin-like modifier) E3-ligase activity, modulates biological processes such as dopaminergic transmission, alters gene expression, and acts as an inhibitor of motor stimuli in the brain striatum. Mutations in the Rhes gene have also been identified in selected patients with autism and schizophrenia. Moreover, Rhes SUMOylates pathogenic form of mutant huntingtin (mHTT) and tau, enhancing their solubility and cell toxicity in Huntington's disease and tauopathy models. Notably, Rhes uses membrane projections resembling tunneling nanotubes to transport mHTT between cells and Rhes deletion diminishes mHTT spread in the brain. Thus, we predict that effective strategies aimed at diminishing brain Rhes levels will prevent or minimize the abnormalities that occur in HD and tauopathies and potentially in other brain disorders. We review the emerging technologies that enable specific targeting of Rhes in the brain to develop effective disease-modifying therapeutics.

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[1]
Napolitano F, D’Angelo L, de Girolamo P, Avallone L, de Lange P, Usiello A. The thyroid hormone-target gene rhes a novel crossroad for neurological and psychiatric disorders: New insights from animal models. Neuroscience 2018; 384: 419-28.
[http://dx.doi.org/10.1016/j.neuroscience.2018.05.027] [PMID: 29857029]
[2]
Harrison LM, LaHoste GJ, Ruskin DN. Ontogeny and dopaminergic regulation in brain of Ras homolog enriched in striatum (Rhes). Brain Res 2008; 1245: 16-25.
[http://dx.doi.org/10.1016/j.brainres.2008.09.066] [PMID: 18929545]
[3]
Vargiu P, Abajo RD, Garcia-Ranea JA, et al. The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors. Oncogene 2004; 23(2): 559-68.
[http://dx.doi.org/10.1038/sj.onc.1207161] [PMID: 14724584]
[4]
Subramaniam S, Mealer RG, Sixt KM, Barrow RK, Usiello A, Snyder SH. Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9. J Biol Chem 2010; 285(27): 20428-32.
[http://dx.doi.org/10.1074/jbc.C110.127191] [PMID: 20424159]
[5]
Subramaniam S, Snyder SH. Huntington’s Disease is a disorder of the corpus striatum: Focus on Rhes (Ras homologue enriched in the striatum). Neuropharmacology 2011; 60(7-8): 1187-92.
[http://dx.doi.org/10.1016/j.neuropharm.2010.10.025] [PMID: 21044641]
[6]
Oscar RMS, Neelam S, Ramírez-Jarquín UN. Rhes, a Striatal Enriched Protein, Regulates Post-Translational Small-Ubiquitin-like-Modifier (SUMO) Modification of Nuclear Proteins and Alters Gene Expression. BioRxiv 2020; 2020; 160044.
[http://dx.doi.org/10.1101/2020.06.18.160044]
[7]
Subramaniam S. Striatal induction and spread of the Huntington’s disease protein: A Novel Rhes Route. J Huntingtons Dis 2022; 11(3): 281-90.
[http://dx.doi.org/10.3233/JHD-220548] [PMID: 35871361]
[8]
Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 2009; 324(5932): 1327-30.
[http://dx.doi.org/10.1126/science.1172871] [PMID: 19498170]
[9]
Shahani N, Swarnkar S, Giovinazzo V, et al. RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network (“Rhesactome”) in the striatum. Sci Signal 2016; 9(454): ra111.
[http://dx.doi.org/10.1126/scisignal.aaf6670] [PMID: 27902448]
[10]
Hernandez J, Shahani N, Swarnkar S, Subramaniam S. Rhes deletion prevents age-dependent selective motor deficits and reduces phosphorylation of S6K in Huntington disease Hdh150Q (CAG) Knock-In Mice. BioRxiv 2021.
[http://dx.doi.org/10.1101/2021.06.16.448681]
[11]
Swarnkar S, Chen Y, Pryor WM, Shahani N, Page DT, Subramaniam S. Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington’s disease. Neurobiol Dis 2015; 82: 66-77.
[http://dx.doi.org/10.1016/j.nbd.2015.05.011] [PMID: 26048156]
[12]
Okamoto S, Pouladi MA, Talantova M, et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 2009; 15(12): 1407-13.
[PMID: 19915593]
[13]
Seredenina T, Gokce O, Luthi-Carter R. Decreased striatal RGS2 expression is neuroprotective in Huntington’s disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation. PLoS One 2011; 6(7): e22231.
[http://dx.doi.org/10.1371/journal.pone.0022231] [PMID: 21779398]
[14]
Baiamonte BA, Lee FA, Brewer ST, Spano D, LaHoste GJ. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington’s disease. PLoS One 2013; 8(1): e53606.
[http://dx.doi.org/10.1371/journal.pone.0053606] [PMID: 23349722]
[15]
Sbodio JI, Paul BD, Machamer CE, Snyder SH. Golgi protein ACBD3 mediates neurotoxicity associated with Huntington’s disease. Cell Rep 2013; 4(5): 890-7.
[http://dx.doi.org/10.1016/j.celrep.2013.08.001] [PMID: 24012756]
[16]
Lu B, Palacino J. A novel human embryonic stem cell‐derived Huntington’s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT‐dependent neurodegeneration. FASEB J 2013; 27(5): 1820-9.
[http://dx.doi.org/10.1096/fj.12-219220] [PMID: 23325320]
[17]
Argenti M. The role of mitochondrial dysfunction in Huntington’s Disease pathogenesis and its relation with striatal Rhes protein 2014.
[18]
Douaud G, Gaura V, Ribeiro MJ, et al. Distribution of grey matter atrophy in Huntington’s disease patients: A combined ROI-based and voxel-based morphometric study. Neuroimage 2006; 32(4): 1562-75.
[http://dx.doi.org/10.1016/j.neuroimage.2006.05.057] [PMID: 16875847]
[19]
Poudel GR, Stout JC, Domínguez DJF, et al. White matter connectivity reflects clinical and cognitive status in Huntington’s disease. Neurobiol Dis 2014; 65: 180-7.
[http://dx.doi.org/10.1016/j.nbd.2014.01.013] [PMID: 24480090]
[20]
Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: Analysis of 36-month observational data. Lancet Neurol 2013; 12(7): 637-49.
[http://dx.doi.org/10.1016/S1474-4422(13)70088-7] [PMID: 23664844]
[21]
Ruocco HH, Bonilha L, Li LM, Lopes-Cendes I, Cendes F. Longitudinal analysis of regional grey matter loss in Huntington disease: Effects of the length of the expanded CAG repeat. J Neurol Neurosurg Psychiatry 2008; 79(2): 130-5.
[http://dx.doi.org/10.1136/jnnp.2007.116244] [PMID: 17615168]
[22]
Aylward EH, Nopoulos PC, Ross CA, et al. Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry 2011; 82(4): 405-10.
[http://dx.doi.org/10.1136/jnnp.2010.208264] [PMID: 20884680]
[23]
Poudel GR, Harding IH, Egan GF, Georgiou-Karistianis N. Network spread determines severity of degeneration and disconnection in Huntington’s disease. Hum Brain Mapp 2019; 40(14): 4192-201.
[http://dx.doi.org/10.1002/hbm.24695] [PMID: 31187915]
[24]
Gerdes HH, Bukoreshtliev NV, Barroso JFV. Tunneling nanotubes: A new route for the exchange of components between animal cells. FEBS Lett 2007; 581(11): 2194-201.
[http://dx.doi.org/10.1016/j.febslet.2007.03.071] [PMID: 17433307]
[25]
Zurzolo C. Tunneling nanotubes: Reshaping connectivity. Curr Opin Cell Biol 2021; 71: 139-47.
[http://dx.doi.org/10.1016/j.ceb.2021.03.003] [PMID: 33866130]
[26]
Brunt L, Greicius G, Rogers S, et al. Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling. Nat Commun 2021; 12(1): 2058.
[http://dx.doi.org/10.1038/s41467-021-22393-9] [PMID: 33824332]
[27]
Korenkova O, Pepe A, Zurzolo C. Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges? Cell Stress 2020; 4(2): 30-43.
[http://dx.doi.org/10.15698/cst2020.02.212] [PMID: 32043076]
[28]
Wood BM, Baena V, Huang H, Jorgens DM, Terasaki M, Kornberg TB. Cytonemes with complex geometries and composition extend into invaginations of target cells. J Cell Biol 2021; 220(5): e202101116.
[http://dx.doi.org/10.1083/jcb.202101116] [PMID: 33734293]
[29]
Zhu C, Shi Y, You J. Immune cell connection by tunneling nanotubes: the impact of intercellular cross-talk on the immune response and its therapeutic applications. Mol Pharm 2021; 18(3): 772-86.
[http://dx.doi.org/10.1021/acs.molpharmaceut.0c01248] [PMID: 33529022]
[30]
Zaccard CR, Rinaldo CR, Mailliard RB. Linked in: Immunologic membrane nanotube networks. J Leukoc Biol 2016; 100(1): 81-94.
[http://dx.doi.org/10.1189/jlb.4VMR0915-395R] [PMID: 26931578]
[31]
Watkins SC, Salter RD. Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity 2005; 23(3): 309-18.
[http://dx.doi.org/10.1016/j.immuni.2005.08.009] [PMID: 16169503]
[32]
Alarcon-Martinez L, Villafranca-Baughman D, Quintero H, et al. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 2020; 585(7823): 91-5.
[http://dx.doi.org/10.1038/s41586-020-2589-x] [PMID: 32788726]
[33]
Zurzolo C. Evidence that tunnelling nanotube-like structures connect cells in mice. Nature 2020; 585(7823): 32-3.
[http://dx.doi.org/10.1038/d41586-020-02315-3] [PMID: 32788697]
[34]
Rostami J, Fotaki G, Sirois J, et al. Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J Neuroinflammation 2020; 17(1): 119.
[http://dx.doi.org/10.1186/s12974-020-01776-7] [PMID: 32299492]
[35]
Zhao J, Wu H, Tang X. Tau internalization: A complex step in tau propagation. Ageing Res Rev 2021; 67: 101272.
[http://dx.doi.org/10.1016/j.arr.2021.101272] [PMID: 33571704]
[36]
Ljubojevic N, Henderson JM, Zurzolo C. The ways of actin: Why tunneling nanotubes are unique cell protrusions. Trends Cell Biol 2021; 31(2): 130-42.
[http://dx.doi.org/10.1016/j.tcb.2020.11.008] [PMID: 33309107]
[37]
Martins-Marques T, Hausenloy DJ, Sluijter JPG, Leybaert L, Girao H. Intercellular Communication in the Heart: Therapeutic Opportunities for Cardiac Ischemia. Trends Mol Med 2020. Epub 2020/11/04.
[http://dx.doi.org/10.1016/j.molmed.2020.10.002] [PMID: 33139169]
[38]
Auguste M, Balbi T, Ciacci C, Canesi L. Conservation of cell communication systems in invertebrate host-defence mechanisms: Possible role in immunity and disease. Biology 2020; 9(8): 234.
[http://dx.doi.org/10.3390/biology9080234] [PMID: 32824821]
[39]
Subramaniam S. Rhes tunnels: A radical new way of communication in the brain’s striatum? BioEssays 2020; 42(6): 1900231.
[http://dx.doi.org/10.1002/bies.201900231] [PMID: 32236969]
[40]
Pinto G, Brou C, Zurzolo C. Tunneling nanotubes: The fuel of tumor progression? Trends Cancer 2020; 6(10): 874-88.
[http://dx.doi.org/10.1016/j.trecan.2020.04.012] [PMID: 32471688]
[41]
Scheiblich H, Dansokho C, Mercan D, et al. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 2021; 184(20): 5089-5106.e21.
[http://dx.doi.org/10.1016/j.cell.2021.09.007] [PMID: 34555357]
[42]
Valdinocci D, Radford R, Siow S, Chung R, Pountney D. Potential modes of intercellular α-synuclein transmission. Int J Mol Sci 2017; 18(2): 469.
[http://dx.doi.org/10.3390/ijms18020469] [PMID: 28241427]
[43]
Sharma M, Jarquín UNR, Rivera O, et al. Rhes, a striatal-enriched protein, promotes mitophagy via Nix. Proc Natl Acad Sci 2019; 116(47): 23760-71.
[http://dx.doi.org/10.1073/pnas.1912868116] [PMID: 31676548]
[44]
Sharma M, Subramaniam S. Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion. J Cell Biol 2019; 218(6): 1972-93.
[http://dx.doi.org/10.1083/jcb.201807068] [PMID: 31076452]
[45]
Ehrenberg AJ, Leng K, Letourneau KN, et al. Patterns of neuronal Rhes as a novel hallmark of tauopathies. Acta Neuropathol 2021; 141(5): 651-66.
[http://dx.doi.org/10.1007/s00401-021-02279-2] [PMID: 33677647]
[46]
Hernandez I, Luna G, Rauch JN, et al. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med 2019; 11(485): eaat3005.
[http://dx.doi.org/10.1126/scitranslmed.aat3005] [PMID: 30918111]
[47]
Liu YL, Fann CSJ, Liu CM, et al. RASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function. Biol Psychiatry 2008; 64(9): 789-96.
[http://dx.doi.org/10.1016/j.biopsych.2008.04.035] [PMID: 18571626]
[48]
Yang HC, Liu CM, Liu YL, et al. The DAO gene is associated with schizophrenia and interacts with other genes in the Taiwan Han Chinese population. PLoS One 2013; 8(3): e60099.
[http://dx.doi.org/10.1371/journal.pone.0060099] [PMID: 23555897]
[49]
Vadgama N, Pittman A, Simpson M, et al. De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes. Eur J Hum Genet 2019; 27(7): 1121-33.
[http://dx.doi.org/10.1038/s41431-019-0376-7] [PMID: 30886340]
[50]
Zaczek R, Simonton S, Coyle JT. Local and distant neuronal degeneration following intrastriatal injection of kainic acid. J Neuropathol Exp Neurol 1980; 39(3): 245-64.
[http://dx.doi.org/10.1097/00005072-198005000-00003] [PMID: 6154134]
[51]
Coyle JT, Schwarcz R. The discovery and characterization of targeted perikaryal-specific brain lesions with excitotoxins. Front Neurosci 2020; 14: 927.
[http://dx.doi.org/10.3389/fnins.2020.00927] [PMID: 33013307]
[52]
Mattson MP, Guthrie PB, Kater SB. Intrinsic factors in the selective vulnerability of hippocampal pyramidal neurons. Prog Clin Biol Res 1989; 317: 333-51.
[PMID: 2690106]
[53]
Rasia-Filho AA, Guerra KTK, Vásquez CE, et al. The subcortical-allocortical- neocortical continuum for the emergence and morphological heterogeneity of pyramidal neurons in the human brain. Front Synaptic Neurosci 2021; 13: 616607.
[http://dx.doi.org/10.3389/fnsyn.2021.616607] [PMID: 33776739]
[54]
Sims NR. Energy metabolism and selective neuronal vulnerability following global cerebral ischemia. Neurochem Res 1992; 17(9): 923-31.
[http://dx.doi.org/10.1007/BF00993269] [PMID: 1407279]
[55]
Schreiber SS, Baudry M. Selective neuronal vulnerability in the hippocampus - a role for gene expression? Trends Neurosci 1995; 18(10): 446-51.
[http://dx.doi.org/10.1016/0166-2236(95)94495-Q] [PMID: 8545911]
[56]
Grilli M, Diodato E, Lozza G, et al. Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically. Proc Natl Acad Sci USA 2000; 97(23): 12822-7.
[http://dx.doi.org/10.1073/pnas.97.23.12822] [PMID: 11070093]
[57]
Calabresi P, Centonze D, Gubellini P, et al. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog Neurobiol 2000; 61(3): 231-65.
[http://dx.doi.org/10.1016/S0301-0082(99)00030-1] [PMID: 10727775]
[58]
Saulle E, Gubellini P, Picconi B, et al. Neuronal vulnerability following inhibition of mitochondrial complex II: A possible ionic mechanism for Huntington’s disease. Mol Cell Neurosci 2004; 25(1): 9-20.
[http://dx.doi.org/10.1016/j.mcn.2003.09.013] [PMID: 14962736]
[59]
Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord 2013; 28(1): 41-50.
[http://dx.doi.org/10.1002/mds.25095] [PMID: 22791686]
[60]
Pons-Espinal M, Blasco-Agell L, Consiglio A. Dissecting the non-neuronal cell contribution to Parkinson’s disease pathogenesis using induced pluripotent stem cells. Cell Mol Life Sci 2021; 78(5): 2081-94.
[http://dx.doi.org/10.1007/s00018-020-03700-x] [PMID: 33210214]
[61]
Gonzalez-Rodriguez P, Zampese E, Surmeier DJ. Selective neuronal vulnerability in Parkinson’s disease Prog Brain Res. 2020; 252: p. 61-89.
[http://dx.doi.org/10.1016/bs.pbr.2020.02.005] [PMID: 32247375]
[62]
Fairless R, Williams SK, Diem R. Calcium-binding proteins as determinants of central nervous system neuronal vulnerability to disease. Int J Mol Sci 2019; 20(9): 2146.
[http://dx.doi.org/10.3390/ijms20092146] [PMID: 31052285]
[63]
Subramaniam S. Selective neuronal death in neurodegenerative diseases: The ongoing mystery. Yale J Biol Med 2019; 92(4): 695-705.
[PMID: 31866784]
[64]
Ball MJ. Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study. Acta Neuropathol 1978; 42(2): 73-80.
[http://dx.doi.org/10.1007/BF00690970] [PMID: 654888]
[65]
Chen XQ, Mobley WC. Alzheimer disease pathogenesis: Insights from molecular and cellular biology studies of oligomeric aβ and tau species. Front Neurosci 2019; 13: 659.
[http://dx.doi.org/10.3389/fnins.2019.00659] [PMID: 31293377]
[66]
Jellinger K. Neuropathological substrates of Alzheimer’s disease and Parkinson’s disease. J Neural Transm Suppl 1987; 24: 109-29.
[PMID: 3316494]
[67]
Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci 1987; 84(16): 5976-80.
[http://dx.doi.org/10.1073/pnas.84.16.5976] [PMID: 3475716]
[68]
Minakaki G, Krainc D, Burbulla LF. The Convergence of alpha-synuclein, mitochondrial, and lysosomal pathways in vulnerability of midbrain dopaminergic neurons in Parkinson’s disease. Front Cell Dev Biol 2020; 8: 580634.
[http://dx.doi.org/10.3389/fcell.2020.580634] [PMID: 33381501]
[69]
Nishiyama K, Murayama S, Goto J, et al. Regional and cellular expression of the machado-joseph disease gene in brains of normal and affected individuals. Ann Neurol 1996; 40(5): 776-81.
[http://dx.doi.org/10.1002/ana.410400514] [PMID: 8957019]
[70]
Tomioka I, Nagai Y, Seki K. Generation of common marmoset model lines of spinocerebellar ataxia type 3. Front Neurosci 2020; 14: 548002.
[http://dx.doi.org/10.3389/fnins.2020.548002] [PMID: 33071733]
[71]
Bergonzoni G, Döring J, Biagioli M. D1R- and D2R-medium-sized spiny neurons diversity: Insights into striatal vulnerability to Huntington’s disease mutation. Front Cell Neurosci 2021; 15: 628010.
[http://dx.doi.org/10.3389/fncel.2021.628010] [PMID: 33642998]
[72]
Katsuno M, Tanaka F, Adachi H, et al. Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA). Prog Neurobiol 2012; 99(3): 246-56.
[http://dx.doi.org/10.1016/j.pneurobio.2012.05.007] [PMID: 22609045]
[73]
Pievani M, Bocchetta M, Boccardi M, et al. Striatal morphology in early-onset and late-onset Alzheimer’s disease: A preliminary study. Neurobiol Aging 2013; 34(7): 1728-39.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.01.016] [PMID: 23428181]
[74]
Hanseeuw BJ, Lopera F, Sperling RA, et al. Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 17.
[http://dx.doi.org/10.1186/s13195-019-0468-1] [PMID: 30717814]
[75]
Selden N, Mesulam MM, Geula C. Human striatum: The distribution of neurofibrillary tangles in Alzheimer’s disease. Brain Res 1994; 648(2): 327-31.
[http://dx.doi.org/10.1016/0006-8993(94)91136-3] [PMID: 7922549]
[76]
Hamasaki H, Honda H, Suzuki SO, et al. Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer’s disease: The Hisayama study. Alzheimers Dement 2019; 11(1): 415-23.
[http://dx.doi.org/10.1016/j.dadm.2019.04.008] [PMID: 31206007]
[77]
Iwasaki Y. The Braak hypothesis in prion disease with a focus on Creutzfeldt–Jakob disease. Neuropathology 2020; 40(5): 436-49.
[http://dx.doi.org/10.1111/neup.12654] [PMID: 32363728]
[78]
Vargiu P, Morte B, Manzano J, et al. Thyroid hormone regulation of rhes, a novel Ras homolog gene expressed in the striatum. Brain Res Mol Brain Res 2001; 94(1-2): 1-8.
[http://dx.doi.org/10.1016/S0169-328X(01)00140-1] [PMID: 11597759]
[79]
Carbo M, Brandi V, Pascarella G, et al. Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington’s disease therapy. Int J Mol Med 2019; 44(6): 2223-33.
[http://dx.doi.org/10.3892/ijmm.2019.4373] [PMID: 31638189]
[80]
Errico F, Santini E, Migliarini S, et al. The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons. Mol Cell Neurosci 2008; 37(2): 335-45.
[http://dx.doi.org/10.1016/j.mcn.2007.10.007] [PMID: 18035555]
[81]
Sciamanna G, Napolitano F, Pelosi B, et al. Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons. Neurobiol Dis 2015; 78: 146-61.
[http://dx.doi.org/10.1016/j.nbd.2015.03.021] [PMID: 25818655]
[82]
Napolitano F, De Rosa A, Russo R, et al. The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses. Sci Rep 2019; 9(1): 15294.
[http://dx.doi.org/10.1038/s41598-019-51839-w] [PMID: 31653935]
[83]
Ghiglieri V, Napolitano F, Pelosi B, et al. Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion. Sci Rep 2015; 5(1): 10933.
[http://dx.doi.org/10.1038/srep10933] [PMID: 26190541]
[84]
Brugnoli A, Napolitano F, Usiello A, Morari M. Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato-nigral neurons activation in levodopa-induced dyskinesia. Neurobiol Dis 2016; 85: 155-63.
[http://dx.doi.org/10.1016/j.nbd.2015.10.020] [PMID: 26522958]
[85]
Subramaniam S, et al. Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nat Neurosci 2011; 15(2): 191-3.
[86]
Feyder M, Plewnia C, Lieberman OJ, et al. Involvement of autophagy in levodopa‐induced dyskinesia. Mov Disord 2021; 36(5): 1137-46.
[http://dx.doi.org/10.1002/mds.28480] [PMID: 33460487]
[87]
Mealer RG, Murray AJ, Shahani N, Subramaniam S, Snyder SH. Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J Biol Chem 2014; 289(6): 3547-54.
[http://dx.doi.org/10.1074/jbc.M113.536912] [PMID: 24324270]
[88]
Cheah JH, Kim SF, Hester LD, et al. NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 2006; 51(4): 431-40.
[http://dx.doi.org/10.1016/j.neuron.2006.07.011] [PMID: 16908409]
[89]
O’Rourke JG, Gareau JR, Ochaba J, et al. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 2013; 4(2): 362-75.
[http://dx.doi.org/10.1016/j.celrep.2013.06.034] [PMID: 23871671]
[90]
Steffan JS, Agrawal N, Pallos J, et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Science 2004; 304(5667): 100-4.
[http://dx.doi.org/10.1126/science.1092194] [PMID: 15064418]
[91]
Liu Q, Cheng S, Yang H, et al. Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice. Proc Natl Acad Sci USA 2020; 117(33): 20265-73.
[http://dx.doi.org/10.1073/pnas.2002283117] [PMID: 32747555]
[92]
Ramirez-Jarquin UN, Sharma M, Zhou W, Shahani N, Subramaniam S. Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease Proc Natl Acad Sci USA 2022; 119(5)
[PMID: 35086928]
[93]
Cicchetti F, Lacroix S, Cisbani G, et al. Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann Neurol 2014; 76(1): 31-42.
[http://dx.doi.org/10.1002/ana.24174] [PMID: 24798518]
[94]
Pecho-Vrieseling E, Rieker C, Fuchs S, et al. Transneuronal propagation of mutant huntingtin contributes to non–cell autonomous pathology in neurons. Nat Neurosci 2014; 17(8): 1064-72.
[http://dx.doi.org/10.1038/nn.3761] [PMID: 25017010]
[95]
Jeon I, Cicchetti F, Cisbani G, et al. Human-to-mouse prion-like propagation of mutant huntingtin protein. Acta Neuropathol 2016; 132(4): 577-92.
[http://dx.doi.org/10.1007/s00401-016-1582-9] [PMID: 27221146]
[96]
Babcock DT, Ganetzky B. Transcellular spreading of huntingtin aggregates in the Drosophila brain. Proc Natl Acad Sci 2015; 112(39): E5427-33.
[http://dx.doi.org/10.1073/pnas.1516217112] [PMID: 26351672]
[97]
Pearce MMP, Spartz EJ, Hong W, Luo L, Kopito RR. Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat Commun 2015; 6(1): 6768.
[http://dx.doi.org/10.1038/ncomms7768] [PMID: 25866135]
[98]
Donnelly KM, DeLorenzo OR, Zaya ADA, et al. Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses. eLife 2020; 9: e58499.
[http://dx.doi.org/10.7554/eLife.58499] [PMID: 32463364]
[99]
Kovacs GG. Invited review: Neuropathology of tauopathies: Principles and practice. Neuropathol Appl Neurobiol 2015; 41(1): 3-23.
[http://dx.doi.org/10.1111/nan.12208] [PMID: 25495175]
[100]
Götz J, Halliday G, Nisbet RM. Molecular pathogenesis of the tauopathies. Annu Rev Pathol 2019; 14(1): 239-61.
[http://dx.doi.org/10.1146/annurev-pathmechdis-012418-012936] [PMID: 30355155]
[101]
Lee CYD, Cantle JP, Yang XW. Genetic manipulations of mutant huntingtin in mice: new insights into Huntington’s disease pathogenesis. FEBS J 2013; 280(18): 4382-94.
[http://dx.doi.org/10.1111/febs.12418] [PMID: 23829302]
[102]
Gray M, et al. “Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice,” (in eng). J Neurosci 2008; 28(24): 6182-95.
[103]
Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington’s disease pathology. Curr Trends Neurol 2011; 5: 65-78.
[PMID: 22180703]
[104]
Rubinsztein DC. How does the Huntington’s disease mutation damage cells? Sci SAGE KE 2003; 2003(37): PE26.
[http://dx.doi.org/10.1126/sageke.2003.37.pe26] [PMID: 13679594]
[105]
Ehrenberg AJ, Leng K, Letourneau KN, et al. Patterns of neuronal Rhes as a novel hallmark of tauopathies Acta Neuropathol 2021; 141(5): 651-66.
[PMID: 33677647]
[106]
Lee JH, Sowada MJ, Boudreau RL, et al. Rhes suppression enhances disease phenotypes in Huntington’s disease mice. J Huntingtons Dis 2014; 3(1): 65-71.
[http://dx.doi.org/10.3233/JHD-140094] [PMID: 25062765]
[107]
Pryor WM, Biagioli M, Shahani N, et al. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Sci Signal 2014; 7(349): ra103.
[http://dx.doi.org/10.1126/scisignal.2005633] [PMID: 25351248]
[108]
Caballero B, Bourdenx M, Luengo E, et al. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun 2021; 12(1): 2238.
[http://dx.doi.org/10.1038/s41467-021-22501-9] [PMID: 33854069]
[109]
Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting Huntingtin Expression in patients with Huntington’s Disease. N Engl J Med 2019; 380(24): 2307-16.
[http://dx.doi.org/10.1056/NEJMoa1900907] [PMID: 31059641]
[110]
Marxreiter F, Stemick J, Kohl Z. Huntingtin lowering strategies. Int J Mol Sci 2020; 21(6): 2146.
[http://dx.doi.org/10.3390/ijms21062146] [PMID: 32245050]
[111]
Swarup V, Hinz FI, Rexach JE, et al. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nat Med 2019; 25(1): 152-64.
[http://dx.doi.org/10.1038/s41591-018-0223-3] [PMID: 30510257]
[112]
Dhindsa RS, Zoghbi AW, Krizay DK, Vasavda C, Goldstein DB. A transcriptome‐based drug discovery paradigm for neurodevelopmental disorders. Ann Neurol 2021; 89(2): 199-211.
[http://dx.doi.org/10.1002/ana.25950] [PMID: 33159466]

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